1. Field of the Invention
The invention is in the field of cell adhesion proteins. Specifically, the invention is in the field of CLEVER-1, a novel protein that facilitates the influx of leukocytes and malignant cells into the lymphatic system, and also the efflux of the same out of the lymph nodes.
2. Background Art
Leukocytes are the major cellular components of inflammatory and immune responses. Leukocytes include lymphocytes, natural killer (NK) cells, monocytes, dendritic cells and granulocytes (neutrophils, eosinophils and basophils). See, HARRISON'S PRINCIPLES OF INTERNAL MEDICINE, Fauci, A. S. et al. eds. (14th ed. 1998). Lymphocytes are composed of B cells and T cells. B cells provide humoral immunity and are the precursors of plasma cells. T cells provide cell mediated immunity. In tissues monocytes differentiate further into macrophages. At sites of inflammation, blood monocytes can attach to inflamed endothelia. Macrophages recognize and take up a wide range of exogenous materials such as bacteria. Granulocytes also have critical roles in inflammation. They are needed to clear infections with extracellular bacteria. The immune response has an important role in the growth, differentiation, and mobilization of granulocytes.
Continuous lymphocyte recirculation between blood and lymphoid tissues forms a basis for the function of the immune system. However such lymphocyte recirculation inadvertently also facilitates at least two medical conditions: inflammation and metastasis.
Lymphocytes enter the lymphoid tissues by binding to vascular endothelial cells. Lymphocyte adherence to endothelial cells is mediated by complementary, surface expressed molecules on both cell types. The adhesion molecules and mechanisms of lymphocyte entrance into the tissues from the blood have been thoroughly characterized, but mechanisms controlling lymphocyte exit from the non-lymphoid and lymphoid tissues via lymphatics have remained unknown.
The majority of lymphocytes extravasate into the lymph nodes via specialized vessels called high endothelial venules, or HEV. The rest of the incoming lymphocytes enter the nodes via afferent lymphatics together with antigens and other types of hematopoietic cells such as dendritic cells, macrophages and granulocytes. However, only lymphocytes are able to leave the nodes via the efferent lymphatic system by first traversing the sinusoidal endothelium and then entering the efferent lymphatic vessel. To maintain the homeostasis in the lymph node the numbers of entering and exiting lymphocytes need to be well balanced. The molecular mechanisms involved in lymphocyte exit are unknown.
In addition to being of fundamental importance in normal lymphocyte recirculation, the lymphatics also regulate seeding of metastasizing cells in approximately 50% of cancers that use this type of vessel for spreading. Lymph nodes are often the first organ to develop metastases, especially in the case of carcinomas. The design of the lymphatic system makes it relatively easy for malignant tumor cells to enter (Sleeman, J. P., Recent Results Cancer Res. 157:55-81 (2000)), and thus compounds that prevent the entry and exit of malignant tumor cells from the lymphatics have tremendous therapeutic potential.